South Carolina (SC) ranks 3^ in the nation in mortality rates for head and neck squamous cell carcinoma (HNSCC), and exceeds national averages for incidence of HNSCC. In addition, African American (AA) males in SC have a higher incidence of HNSCC than any other racial/gender group, and a mortality rate almost threefold that observed in European (EA) males. This disparity closely parallels data for cervical cancer in African American (AA) and European American (EA) women in the state. Access to health care and early detection most likely play an important role in determining these and other health disparities between AA and EA. However, additional factors may also contribute. Up to 60% of oropharynegeal cancers and 25% of all HNSCC cases are due to high-risk human papillomaviruses (HR HPV). HPV-positive cancers appear to be a distinct disease, characterized by significantly better overall health status, greater response to therapy, and better disease-specific survival, in comparison with HPV-negative cancers. Preliminary evidence indicates that the prevalence of HPV positivity in HNSCC is much lower in AA than in EA patients. This observation may lead to the conclusion that AA men may be particularly susceptible to the more aggressive HPV-negative HNSCC, and this may contribute to the disparity between these two groups. However, while it is generally accepted that HPV positive HNSCC harbor almost exclusively HPV16, data recently obtained in the course of our Carolina Women's Care Study, which investigates the determinants of HR HPV persistence in the genital tract of female college students, point to a different explanation. We find profound differences in the distribution of HPV types that cause persistent infection between EA and AA women: while HPV16 accounts for almost V^ of all persistent infections in EA women, it accounts only for about % of these infections in AA women. Other HPV types, such as HPV52 and HPV59 are well represented in AA, but almost entirely absent in EA women. In addition, the rate of clearance of HR HPV infection is slower in AA than in EA women and, conversely, the rate at which HPV infection is associated with cytological abnormalities is higher in AA women. Hence, we are confronted with a paradox: with regard to genital infections, AA women seem overall more susceptible to HPVmediated disease than EA women, while AA men appear to be more resistant to oral disease mediated by HPV. Among the possible explanations for this apparent paradox, we elected to focus on two possibilities, which we believe are most plausible: 1. One or more additional HR HPV types, other than HPV16, play a significant role in HNSCC of AA patients. If this is the case, then at least one contributing factor to the disparity between EA and AA in HNSCC would be other HR HPV types. We will directly explore this possibility in Aim 1; or 2. Despite the different distribution of HPVs, HPV16 is the only HR HPV type that easily thrives in the oral cavity, and remains the only (or by far the most prevalent) type associated with HNSCC in both AA and EA patients. If this turns out to be the case, the rare occurrence of HPVpositive cancers in AA men may be explained based on the fact that HPV16 is present with about V2 the frequency in AA women than in EA women. Sexual relations still occur predominantly within, rather than across racial groups, and oral sex is less common and has a later onset among AA men and women (see Background and Significance). This finding would still leave open the question as to why HNSCC is more frequent and more deadly in AA men, and warrant an investigation of the molecular nature of the disease in both racial groups, by gene expression profiling (Aim 2). The idea that HNSCC may be a different disease in AA patients is not totally far-fetched, as there is evidence that breast and prostate cancer also develop and behave in distinct ways in the two racial groups (see Background and Significance). Hypothesis: the null hypothesis is that there are no differences in prevalence of HPV infection and type distribution between HNSCC in AA and EA patients. In addition, the study will test whether distinctive gene expression profiles characterize HPV positive and HPV negative cancers between racial groups, helping to shed light on differences in the mechanisms of HNSCC development between the two races. Along these lines, preliminary gene expression studies of HPVpositive and HPVnegative HNSCC (which are ongoing in our laboratory as a part of a seed grant leading to this and other collaborative proposals on HNSCC) identified differentially-expressed genes that may play a role in determining the different pathogenetic and clinical characteristics of these tumors.